Flaxseed and its lignan and oil components: Mechanisms of biological effect

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The long term goal of my research program is to elucidate the cellular and molecular mechanisms whereby flaxseed and its major components, the phytoestrogen lignan and alpha- linolenic acid (ALA)-rich oil, exert their biological effects but the main focus of this proposal is ALA. Our previous studies have shown that ALA-rich flaxseed oil can reduce the growth rate of cancer cells but the extent of change depends on the estrogen environment, whether the cells are estrogen receptor (ER) positive or negative and with no, low or overexpressed HER2 (a type of growth factor receptor), and whether they interact with other bioactive compounds or pharmacologic agents that also bind to HER2. Limited fundamental knowledge on the mechanisms of the effect under those conditions may have contributed to the inconsistencies in biological response to fatty acids. I therefore propose to do basic research on the effect of various levels of ALA on several cell line models that differentially express ER and HER2, alone or in combination with compounds that are able to reduce the expression and activity of HER2 such as trastuzumab (herceptin). Using in vitro methods, those cell lines will be treated with various levels of ALA, alone or combined with trastuzumab, and the following will be measured and correlated in a series of experiments: (a) cell proliferation and apoptosis (programmed cell death), (b) protein and gene expressions of ER, HER2 and molecules involved in cell signalling that leads to cell growth, (c) microRNA, (d) fatty acid synthase and phosphatase and tensin homologue expressions, (e) lipid peroxidation, and (f) cell membrane lipids that may have led to changes in receptor and cell signalling molecules. Results will provide insight into potential targets for controlling the growth of cells with various levels of ER and HER2 and will also provide guidance to nutritionists and food scientists regarding the use of flaxseed and its ALA-rich oil as functional foods.